Connect public, paid and private patent data with Google Patents Public Datasets

Controlled release of pharmaceutically active substances from coacervate microcapsules

Download PDF

Info

Publication number
US5759582A
US5759582A US08695514 US69551496A US5759582A US 5759582 A US5759582 A US 5759582A US 08695514 US08695514 US 08695514 US 69551496 A US69551496 A US 69551496A US 5759582 A US5759582 A US 5759582A
Authority
US
Grant status
Grant
Patent type
Prior art keywords
active
substance
invention
present
pharmaceutically
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US08695514
Inventor
Kam W. Leong
Rosa V. Azhari
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Johns Hopkins University
Original Assignee
Johns Hopkins University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1658Proteins, e.g. albumin, gelatin
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2984Microcapsule with fluid core [includes liposome]

Abstract

A controlled-release pharmaceutical composition comprising a pharmaceutically active water soluble protein, peptide, glycoprotein, or mixture thereof, encapsulated in the form of microspheres by a coating of a crosslinked coacervate of gelatin and chondroitin sulfate, as well as processes for the preparation thereof.

Description

This is a continuation of application Ser. No. 08/431,501, filed Apr. 28, 1995, now abandoned, which is a continuation of application Ser. No. 08/098,574 filed on 7/28/93, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention This invention relates to coacervate-based microcapsules which include pharmaceutically active substances as well as to a method of providing controlled release of such substances in vivo. The microcapsules of the invention are useful to prepare and deliver drugs, biologicals, enzymes, and pharmaceutically active substances.

2. Description of Related Art

A controlled delivery system which will dependably release a biologically active substance (e.g., a pharmaceutical agent) in vivo into a biological fluid (e.g., fluids of gastrointestinal tract) or into body tissues has remained an elusive goal. Biologically active endogenous substances such as cytokines, hormones, enzymes, and antibodies are usually less stable than conventional synthetic drugs in the physiological environment. The controlled delivery system thus provides a suitable means to administer these endogenous substances to a host.

A common approach to providing controlled release of the active substance is the encapsulation of the active substance within a polymer matrix (e.g., that made of hydrophilic polymers). While some combinations of a drug and particular polymers provide a suitable drug release profile, they require relatively large quantities of synthetic materials to be delivered to the body. This is not desirable since such materials or their metabolites in vivo may not be biocompatible or even may have toxicity such as cytotoxicity or mutagenicity. Furthermore, encapsulation involves the use of organic solvents and/or heat, both of which can be harmful to peptide or proteinous drugs, not to mention the above-described endogenous substances.

Complex coacervation is a process of separation of colloidal solutions into two or more immiscible liquid phases. When oppositely charged polyelectrolytes are brought to contact in aqueous medium, a spontaneous phase separation occurs with the result of formation of coacervates. The coacervate is a phase where colloids (e.g., polymers) are concentrated.

Coacervation has been employed to encapsulate water insoluble biologically active substances. For example, U.S. Pat. No. 4,794,000 discloses a method for preparing a pharmaceutical composition for oral administration which is based on two phase coacervate system where erythromycin is included as the active ingredient. U.S. Pat. No. 5,051,304 discloses microcapsules formed by coacervation between gelatin and a chemically depolymerized polysaccharide wherein a variety of water immiscible substances can be included.

While these and other references generally teaches the applicability of the coacervation technique to a delivery system in the form of a coacervate, the coacervate formation to encapsulate a particular substance of interest can only be achieved by carefully controlling the phase separation conditions such as the choice and concentrations of suitable polyelectrolytes, pH and temperature.

Rheumatoid arthritis, which affects 3-4% of the population, is characterized by inflammation and pain of joints. Although the etiology of rheumatoid arthritis is not well elucidated, both steroid and non-steroidal therapy have been used to alleviate the symptoms of this illness. However, gastrointestinal irritation, including ulcers, is a side effect commonly associated, to one degree or another, with antiinflammatory agents. In order to avoid such side effects and to enhance drug concentrations in synovial sites, intra-articular injection is considered a viable method of administration of an anti-inflammatory agent. There appears to be no literature available which suggests coacervate-based microcapsules as a intraarticular form of administration of the anti-inflammatory agent.

The present invention permits desirable chemotherapy, including anti-inflammatory therapy, by providing controlled release of a pharmaceutically active substance into the body while preventing or ameliorating undesirable side effects associated with administration of the substance by a known delivery system.

SUMMARY OF THE INVENTION

In one aspect thereof, the present invention provides a pharmaceutical composition for the controlled release of a pharmaceutically active substance comprising a therapeutically effective amount of the pharmaceutically active substance in the form of microspheres, encapsulated by a coating of a crosslinked coacervate of gelatin and chondroitin sulfate.

In another aspect, the present invention also provides a process for preparing the above-described pharmaceutical composition which comprises the steps of:

(a) providing a gelatin aqueous solution;

(b) providing a chondroitin sulfate aqueous solution;

(c) adding a therapeutically effective amount of a pharmaceutically active substance either to the solution in step (a) or to the solution in step (b);

(d) mixing the gelatin and chondroitin sulfate solutions to form a coacervate suspension;

(e) adding a crosslinking agent to the coacervate suspension to crosslink the coacervates, the coacervates encapsulating the pharmaceutically active substance; and

(f) incubating the coacervate suspension to form microspheres and recovering the microspheres.

In further aspect, the present invention provides a method of releasing a pharmaceutically active substance in vivo in a controlled manner which comprises administering the above-identified pharmaceutical composition to a host and degrading the coacervates by the action of a gelatin-digesting enzyme.

In still further aspect, the present invention provides an encapsulated pharmaceutically active substance. The above features and advantages of the present invention will be more fully understood by reference to the following detailed description and the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photomicrograph of the microspheres prepared in the practice of the present invention.

FIG. 2 shows the in vitro release kinetics of sCR1 when incorporated in the pharmaceutical composition according to the present invention.

FIG. 3 shows the activity of released sCR1 in medium with time in the practice of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In this disclosure, the term "microcapsules" refers to microspheres wherein a pharmaceutically active substance is encapsulated by a coating of coacervates. Specifically useful in the present invention is a solid microsphere which is a matrix type rather than a core-shell type. If the pharmaceutically active substance is a charged molecule such as protein, the molecule is likely to participate in the complex coacervation process to form the microsphere wherein the substance is entangled with the microsphere matrix.

As applied in the present invention, the term "pharmaceutically active substance" is intended to encompass any substance that will produce a therapeutically beneficial pharmacological response when administered to a host, both human and animal. Suitable substances include, but are not restricted to analgesics, antibacterials, antifungals, immunosuppressants, anti-inflammatories, and anti-cancer agents. Some non-limiting examples of antibacterials include penicillins, cephalosporins, tetracyclines, quinolones, and aminoglycosides. Representatives of anti-inflammatories include hydrocortisone, colchicine, ibuprofen, indomethacin, and piroxicam. More than one pharmaceutically active substance may be included, if desired, in the pharmaceutical compositions of the present invention. The active substances may be water-soluble or water-insoluble and may include those having a high molecular weight proteins, peptides, carbohydrates, glycoproteins, lipids, and glycolipids. The process of the present invention is particularly suitable for encapsulation of these high molecular weight, susceptible biomacromolecules.

The pharmaceutically active substance can be employed in the present invention in various forms, such as molecular complexes or pharmaceutically acceptable salts. Representative examples of such salts are succinate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, salicylate, metal salts (e.g., alkali or alkaline earth), ammonium or amine salts (e.g., quaternary ammonium) and the like. Furthermore, derivatives of the active substances such as esters, amides, and ethers which have desirable retention and release characteristics but which are readily hydrolyzed in vivo by physiological pH or enzymes can also be employed.

As used herein, the term "therapeutically effective amount" means that the amount of the pharmaceutically active substance is of sufficient quantity to induce desired pharmacological effect. The amount can vary greatly according to the effectiveness of a particular active substance, the age, weight, and response of the individual host as well as the nature and severity of the host's symptoms. Accordingly, there is no upper or lower critical limitation upon the amount of the active substance. The required quantity to be employed in the present invention can readily be determined by those skilled in the art.

As used herein with respect to the pharmaceutically active substance, the term "controlled release" is intended to mean that the present composition require at least an hour to release a major portion of the active substance into the surrounding medium, e.g. about 1-24 hours or even much longer.

In accordance with the present invention, the pharmaceutically active substance is encapsulated in a coacervate which is reinforced by crosslinking. Components that may be used to form the coacervate comprise anionic and cationic molecules. By "cationic" or "anionic" molecule is meant a molecule which, under the conditions of coacervation, carries a net positive or negative charge. Many such molecules are amphoteric and contain both acidic and basic groups. Under prevailing pH conditions, these molecules can be either cationic or anionic. Cationic molecules include albumin, collagen, elastin, gelatin, and globulins. Anionic molecules include chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, hyaluronic acid, keratan sulfate, polygalacturonic acid, and polyglucuronic acid. The choice of the cationic and anionic molecules depends on the final or intended use of the present compositions and they are expected to possess a high degree of biocompatibility. Preferably, gelatin is used as the cationic molecule in the present invention. Collagen is also preferred as the cationic molecule. Chondroitin sulfate is preferably used as the anionic molecule. Chondroitin sulfate is a mucopolysaccharide found in skeletal and soft connective tissues. The crosslinking is preferably effected by use of a gelatin-harding agent such as glutaraldehyde. Epichlorohydrin and acrolein can also be used as the crosslinking agent. Typically, in preparing the coacervates of the present invention, both types of components are brought into contact in an aqueous medium under predetermined mixing conditions. The mixing can conveniently be carried out using equivolumes of an aqueous gelatin solution and an aqueous chondroitin sulfate solution. Preferably, gelatin is present in the aqueous solution in a concentration of from about 1% to about 10% (w/vol). Chondroitin sulfate is present in the aqueous solution in a concentration of from about 0.05% to about 2% (w/vol). Outside these concentration ranges, the formation of coacervates appears to be adversely effected.

The temperature to be employed in forming coacervates may vary somewhat with the particular method employed. Thus, a temperature from ambient temperature to about 50° C. can normally be used. However, the size of coacervates is susceptible to the temperatures of the two components when they are mixed. The higher the temperature of the gelatin solution, the smaller become the coacervates formed. The pH to be employed in forming coacervates can also vary over a fairly wide range. The yield and size of coacervates are influenced by the pH. Preferably, the pH of from about 3.5 to about 6.5 (the latter of which corresponds to the isoelectric point of gelatin) is used. The pH of the gelation solution predominates over that of the chondroitin solution in determining the pH of the mixture of the two. Optimum results in terms of both the size and yield of the coacervates are obtained at a pH of about 5.0.

The desired amount of the pharmaceutically active substance is added either to the gelatin solution or to the chondroitin sulfate solution prior to the formation of coacervates. If the active substance is water-soluble, a solution results. On the other hand, if the active substance is water-insoluble, an emulsion or suspension results.

Upon mixing of the gelatin solution and the chondroitin sulfate solution with stirring, coacervation takes place in the reaction medium to form coacervates of microsphere. Since a coating of coacervate (walls) is generally too fragile for coacervates to be isolated, the crosslinking of the coacervates is necessary. The crosslinking is preferably carried out by adding to a suspension containing stabilized coacervatecoated microspheres, glutaraldehyde or another gelatin hardener. After completion of the crosslinking reaction, the resulting microspheres are recovered from the reaction medium by a conventional means, e.g., decantation, filtration, or centrifugation. The microspheres may be washed and dried in a standard technique, e.g., lyophilization.

The coacervate-coated microspheres of the present invention preferably have a sphere size (mean diameter) of about 0.5 μm to about 100 μm, and contain about 10% to 40% (w/w) of a pharmaceutically active substance. In other words, the weight ratio of the pharmaceutically active substance to the coacervate (walls) in the microspheres on a dry basis is about from 1:9 to about 2:3. The pharmaceutical compositions based on the coacervate-coated microspheres can be utilized for oral ingestion, implantation, or external application to the skin or a mucous membrane. Where implantation is desired, they can be implanted subcutaneously, constitute a part of a prosthesis, or be inserted in a cavity of the human body. Subcutaneous implantation using a syringe consists of injecting the implant directly into subcutaneous tissue, and is a particularly effective method of controlled drug delivery. This method is viewed as an alternative to surgery where some risk may be encountered. Thus, the microcapsules obtained in the present invention can be suspended in a physiological buffer and introduced via a syringe to the desired site.

For example, the present compositions incorporating hydrocortisone or any other known anti-inflammatory agent can be injected into the region of an inflammatory joint or muscle. As indicated above, a wide variety of pharmaceutical agents can be included in the present compositions and administered to the body in essentially the same manner. Other than anti-inflammatories, the delivery of narcotic antagonists, contraceptive or anabolic steroids, and anticancer agents can be contemplated. Narcotic antagonists, such as naltrexone, cyclazocine, and naloxone, are therapeutically useful in the postdetoxification stage of rehabilitation of drug-dependent patients. Steroids which can be used are, for example, progesterone and estradiol. Anticancer agents which can be used include cyclophosphamide, 5-fluorouracil (5-FU), doxorubicin, and cisplatin. Additionally, intravaginal or intraureteral implants based on the present compositions may be useful for the delivery of contraceptives and other drugs.

Upon application to the desired part of the body by the desired mode, the pharmaceutical compositions of the present invention provide controlled release of the pharmaceutically active substance by allowing it to diffuse through the coacervate walls of microspheres or by allowing the coacervate to degrade in vivo upon contact with body fluids. When the coacervate is degradable in the site (e.g., tissue or joint) where the composition is delivered, the degree of its degradation (i.e., the release rate of the active substance) can be regulated by the crosslinking degree of the coacervate.

The microcapsules of the present invention is premised primarily upon components which are found endogenous to the human body, whether natural or synthetic. The present invention thus makes it possible to employ significantly lesser quantities of non-biological materials than generally used in preparing controlled release pharmaceutical compositions. This high level of biocompatibility reflects in the absence of cytotoxicity and immunogenicity and the lack of causation of inflammation and foreign body reaction.

The following non-limiting examples are provided to further illustrate the present invention.

EXAMPLE 1

In this example, the following reagents and solvent were used: Gelatin (type A, 60 bloom; Sigma, St. Louis, Mo.), chondroitin-4-sulfate (Sigma), glutaraldehyde (Sigma), collagenase (type VII; Sigma), fluorescein isothiocyanate (FITC; Sigma), sCR1 (T Cell Sciences, Cambridge, Mass.), 2,2'-azino-di- 3-ethyl benzthioazoline-6-sulfonic acid! (ABTS; Bio-Rad, Hercules, Calif.), and sheep red blood cells (Thomas D. Morris, Inc., Philadelphia, Pa.).

sCR1 (22 mg) was dissolved in 5 ml of 0.2% (w/v) chondroitin sulfate in distilled water at ambient temperature. An equal volume of 5% (w/v) gelatin in distilled water at 37° C. was added to the chondroitin sulfate solution. Upon mixing by a vortex mixer, a suspension was obtained and this was stirred for 10 minutes. Glutaraldehyde (5 μl/ml) in distilled water was added to the suspension. The mixture was shaken in a rotary shaker for 30 minutes at room temperature. Ethanolamine-HCI (pH 9.0, 0.6 ml/ml solution) was added to the mixture in order to quench the excess glutaraldehyde. The resulting mixture was allowed to stand overnight at 0° C., precipitating microparticles. The microparticles were collected, washed with phosphate buffered saline solution (PBS; 0.01M, pH 7.4), and dried.

The morphology of the microparticles' surface was determined by scanning electron microscope (SEM). Samples were dried using CO2 critical point drying and then sputter coated with gold. SEM images were taken at 20 to 30KV on an Amray 1810 microscope. Under SEM, the microparticles were determined to be spherical and to have a particle size of between 5 μm and 30 μm.

The amount of sCR1 encapsulated in the microspheres was determined by analysis in solution before and after encapsulation. The analysis was conducted according to an ELISA procedure using monoclonal Mouse IgGI anti-sCR1 and a peroxidase conjugate of Sheep anti-Mouse IgG. ABTS was used as the peroxidase substrate. Thus, a sCR loding level of about 35% (w/w) was determined.

A confocal microscope (Bio-Rad MRC-600 microscope) study was undertaken to determine the distribution of sCR1 within the microsphere.

For this purpose, fluorescein labelled sCR1 was synthesized by addition of 5 mg of FITC (dissolved in 0.5 ml of acetone) to 3.6 mg of sCR1 in 3 nl of 0.1M sodium bicarbonate. After reaction at room temperature for 15 minutes and at 0° C. overnight, the mixture was dialyzed against water and lyophilized.

sCR-FITC was encapsulated substantially in the same manner as that described above. A photomicrograph of the microsphere showed that sCR1 -FITC is uniformly distributed throughout the microsphere with a slightly lower concentration toward the outer surface.

A similar analysis using FITC-labelled gelatin showed that the microspheres are of a matrix type and not a core and shell type.

sCR1 is a recombinant, soluble, human complement receptor 1 (CR1) which has been shown to retain the activity of CR1 both in vitro and in vivo (J. M. Ahearn, et al., Advances in Immunology, 1989, 46, 183-219; H. F. Weisman, et al., Science, 1990, 249, 146-151). CR1 is an endogenous regulatory protein that blocks proteolytic enzymes which activate complement proteins C3 and C5. Administration of sCR1 will interfere with the complement activation, thus averting destructive biological processes which lead to inflammation and damage to cartilages. sCR1 is a high molecular weight (200 KD) protein with a half life shorter than 15 minutes at physiological conditions. Thus, the use of sCR1 in its native form as an anti-rheumatic agent will require frequent intra-articular injections. Encapsulation of the protein within microspheres can provide adequate protection in the joint cavity, introduce controlled release features and reduce the frequency of intra-articular injections needed.

EXAMPLE 2 IN VITRO DRUG RELEASE FROM MICROSPHERES

Release experiments were conducted in 20 ml of PBS containing 0.36 mM calcium chloride and 10 units of collagenase. The microspheres prepared according to the procedure of EXAMPLE 1 (27 mg dry weight) were suspended in the PBS solution and incubated at 37° C. Control samples were also prepared in the absence of collagenase.

Sample aliquots were withdrawn from the incubated mixture at different times and placed in a tube containing 100 μl of 0.1M EDTA solution. Released sCR1 was measured by ELISA as described above. The activity of sCR1 was determined by the inhibition of complement activation as measured by the lysis of sensitized sheep red blood cells (SRBC) (H. F. Weisman, et al., op. cit.). The protein was found to maintain its ability throughout the release period. The control samples showed that no sCR1 was released during one week. The in vitro release of sCR1 from the microspheres was thus determined as a function of time. The results of the test are shown in FIGS. 2 and 3.

A model experiment using a biological inactive protein indicated that the protein release was dependent upon the level of collagenase. In a joint cavity where inflammation progresses, the level of collagenase is known to rise (J. Menzel, et al., Z. Rheumatol., 1977, 36, 364-377). Thus, the increased level of collagenase would facilitate in vivo degradation of the microspheres of the present invention in inflammatory lesions.

The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made without departing from the spirit or scope of the invention.

Claims (6)

We claim:
1. A method of releasing a water soluble pharmaceutically active substance selected from the group consisting of a protein, a peptide, and a glycoprotein, and pharmaceutically acceptable salts and mixtures thereof encapsulated in the form of microspheres by a coating of a crosslinked coacervate of gelatin and chondroitin sulfate wherein the microspheres have a mean diameter of from about 0.5μm to about 100μm and contain from about 10 to about 40 weight percent of the pharmaceutically active substance in vivo in a controlled manner to a host and degrading the coacervates by the action of a collagenase.
2. The method according to claim 1, wherein the crosslinked coacervate is glutaraldehyde-crosslinked.
3. The method according to claim 1, wherein the administration is parenteral.
4. The method according to claim 3, wherein the administration is subcutaneous.
5. The method according to claim 3, wherein the administration is intra-articular.
6. The method according to claim 5, wherein the host is in need of treatment of rheumatoid arthritis.
US08695514 1993-07-28 1996-08-12 Controlled release of pharmaceutically active substances from coacervate microcapsules Expired - Fee Related US5759582A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US9857493 true 1993-07-28 1993-07-28
US43150195 true 1995-04-28 1995-04-28
US08695514 US5759582A (en) 1993-07-28 1996-08-12 Controlled release of pharmaceutically active substances from coacervate microcapsules

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08695514 US5759582A (en) 1993-07-28 1996-08-12 Controlled release of pharmaceutically active substances from coacervate microcapsules

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US43150195 Continuation 1995-04-28 1995-04-28

Publications (1)

Publication Number Publication Date
US5759582A true US5759582A (en) 1998-06-02

Family

ID=22269926

Family Applications (1)

Application Number Title Priority Date Filing Date
US08695514 Expired - Fee Related US5759582A (en) 1993-07-28 1996-08-12 Controlled release of pharmaceutically active substances from coacervate microcapsules

Country Status (2)

Country Link
US (1) US5759582A (en)
WO (1) WO1995003789A1 (en)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999011196A1 (en) * 1997-09-04 1999-03-11 Point Biomedical Corporation Injectable tissue reconstruction material
US5981719A (en) 1993-03-09 1999-11-09 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US6090925A (en) 1993-03-09 2000-07-18 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US6193970B1 (en) * 1993-12-14 2001-02-27 The Johns Hopkins University School Of Medicine Controlled release of pharmaceutically active substances for immunotherapy
US20030065400A1 (en) * 2001-04-12 2003-04-03 Beam Heather Ann Method and apparatus for engineered regenrative biostructures such as hydroxyapatite substrates for bone healing applications
US6548302B1 (en) 1998-06-18 2003-04-15 Johns Hopkins University School Of Medicine Polymers for delivery of nucleic acids
US6632671B2 (en) 2000-02-28 2003-10-14 Genesegues, Inc. Nanoparticle encapsulation system and method
US20040038303A1 (en) * 2002-04-08 2004-02-26 Unger Gretchen M. Biologic modulations with nanoparticles
WO2005034852A2 (en) 2003-08-26 2005-04-21 Gel-Del Technologies, Inc. Protein biomaterials and biocoacervates and methods of making and using thereof
US20050085922A1 (en) * 2003-10-17 2005-04-21 Shappley Ben R. Shaped filler for implantation into a bone void and methods of manufacture and use thereof
US6916490B1 (en) 1998-07-23 2005-07-12 UAB Research Center Controlled release of bioactive substances
US20050163817A1 (en) * 2002-04-29 2005-07-28 Masters David B. Biomatrix structural containment and fixation systems and methods of use thereof
US20060008478A1 (en) * 2002-04-18 2006-01-12 Tadao Ohno Immunoadjuvant
WO2006023207A2 (en) * 2004-08-19 2006-03-02 The United States Of America As Represented By The Secretary Of Health And Human Services, Nih Coacervate of anionic and cationic polymer forming microparticles for the sustained release of therapeutic agents
US20060167540A1 (en) * 2003-06-17 2006-07-27 Masters David B Encapsulated or coated stent systems
US20070092480A1 (en) * 2003-05-30 2007-04-26 Thijssen Henricus Matheus W M Inducible release vehicles
WO2007077629A1 (en) 2006-01-06 2007-07-12 Cell-Medicine, Inc. Immune adjuvant
WO2009028764A1 (en) * 2007-08-24 2009-03-05 Industry-University Cooperation Foundation Hanyang University Thermo-reversible coacervate combination gels for protein delivery
US20100143487A1 (en) * 2007-12-26 2010-06-10 Gel-Del Technologies, Inc. Biocompatible protein-based particles and methods thereof
WO2010065613A2 (en) 2008-12-03 2010-06-10 The Johns Hopkins University Annexina2 as immunological target
US8871267B2 (en) 1998-09-25 2014-10-28 Gel-Del Technologies, Inc. Protein matrix materials, devices and methods of making and using thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0769063A1 (en) * 1994-06-27 1997-04-23 The Johns Hopkins University Targeted gene delivery system
CN1068227C (en) * 1997-05-29 2001-07-11 武汉迪普生物技术有限公司 Interferon liposome jellies
WO2000004876A9 (en) * 1998-07-23 2000-08-03 Univ Johns Hopkins Med Controlled release of bioactive substances
WO2000041679A1 (en) * 1999-01-13 2000-07-20 Johns Hopkins University School Of Medicine Genetic immunization with co-delivery of nucleic acid and cytokines
FR2857592B1 (en) * 2003-07-18 2006-02-24 Sod Conseils Rech Applic New microparticles FOR PREPARING

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3757004A (en) * 1971-11-19 1973-09-04 Stanford Research Inst Gelatin coacervate fibers
US4178361A (en) * 1973-09-10 1979-12-11 Union Corporation Sustained release pharmaceutical composition
US4794000A (en) * 1987-01-08 1988-12-27 Synthetic Blood Corporation Coacervate-based oral delivery system for medically useful compositions
US4795642A (en) * 1986-05-01 1989-01-03 Pharmacaps, Inc. Gelatin-encapsulated controlled-release composition
US4923645A (en) * 1987-11-16 1990-05-08 Damon Biotech, Inc. Sustained release of encapsulated molecules
US4965007A (en) * 1988-05-10 1990-10-23 Eastman Kodak Company Encapsulated superparamagnetic particles
US5051185A (en) * 1987-11-06 1991-09-24 Asahi Kasei Kogyo K.K. Absorbent of β2 -microglobulin
US5051304A (en) * 1986-12-18 1991-09-24 Societe Anonyme: Mero Rousselot Satia Microcapsules based on gelatin and polysaccharides and process for obtaining same
US5089272A (en) * 1989-03-29 1992-02-18 Snow Brand Milk Products Co., Ltd. Process for producing capsules having a permeability-controllable membrane
US5143724A (en) * 1990-07-09 1992-09-01 Biomatrix, Inc. Biocompatible viscoelastic gel slurries, their preparation and use
US5260002A (en) * 1991-12-23 1993-11-09 Vanderbilt University Method and apparatus for producing uniform polymeric spheres

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3757004A (en) * 1971-11-19 1973-09-04 Stanford Research Inst Gelatin coacervate fibers
US4178361A (en) * 1973-09-10 1979-12-11 Union Corporation Sustained release pharmaceutical composition
US4795642A (en) * 1986-05-01 1989-01-03 Pharmacaps, Inc. Gelatin-encapsulated controlled-release composition
US5051304A (en) * 1986-12-18 1991-09-24 Societe Anonyme: Mero Rousselot Satia Microcapsules based on gelatin and polysaccharides and process for obtaining same
US4794000A (en) * 1987-01-08 1988-12-27 Synthetic Blood Corporation Coacervate-based oral delivery system for medically useful compositions
US5051185A (en) * 1987-11-06 1991-09-24 Asahi Kasei Kogyo K.K. Absorbent of β2 -microglobulin
US4923645A (en) * 1987-11-16 1990-05-08 Damon Biotech, Inc. Sustained release of encapsulated molecules
US4965007A (en) * 1988-05-10 1990-10-23 Eastman Kodak Company Encapsulated superparamagnetic particles
US5089272A (en) * 1989-03-29 1992-02-18 Snow Brand Milk Products Co., Ltd. Process for producing capsules having a permeability-controllable membrane
US5143724A (en) * 1990-07-09 1992-09-01 Biomatrix, Inc. Biocompatible viscoelastic gel slurries, their preparation and use
US5260002A (en) * 1991-12-23 1993-11-09 Vanderbilt University Method and apparatus for producing uniform polymeric spheres

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Azhari, et al., Protein Release from Enzymatically Degradable Chondroitin Sulfate/Gelatin Microspheres, Proceed. Intern. Symp. Control. Rel. Bioact. Master., 18:617 618, 1991, Controlled Release Society, Inc. *
Azhari, et al., Protein Release from Enzymatically-Degradable Chondroitin-Sulfate/Gelatin Microspheres, Proceed. Intern. Symp. Control. Rel. Bioact. Master., 18:617-618, 1991, Controlled Release Society, Inc.

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981719A (en) 1993-03-09 1999-11-09 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US6090925A (en) 1993-03-09 2000-07-18 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US6268053B1 (en) 1993-03-09 2001-07-31 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US6193970B1 (en) * 1993-12-14 2001-02-27 The Johns Hopkins University School Of Medicine Controlled release of pharmaceutically active substances for immunotherapy
WO1999011196A1 (en) * 1997-09-04 1999-03-11 Point Biomedical Corporation Injectable tissue reconstruction material
US6548302B1 (en) 1998-06-18 2003-04-15 Johns Hopkins University School Of Medicine Polymers for delivery of nucleic acids
US6916490B1 (en) 1998-07-23 2005-07-12 UAB Research Center Controlled release of bioactive substances
US8871267B2 (en) 1998-09-25 2014-10-28 Gel-Del Technologies, Inc. Protein matrix materials, devices and methods of making and using thereof
US6632671B2 (en) 2000-02-28 2003-10-14 Genesegues, Inc. Nanoparticle encapsulation system and method
US20030065400A1 (en) * 2001-04-12 2003-04-03 Beam Heather Ann Method and apparatus for engineered regenrative biostructures such as hydroxyapatite substrates for bone healing applications
US7122057B2 (en) 2001-04-12 2006-10-17 Therics, Llc Method and apparatus for engineered regenerative biostructures such as hydroxyapatite substrates for bone healing applications
US20040038303A1 (en) * 2002-04-08 2004-02-26 Unger Gretchen M. Biologic modulations with nanoparticles
US20060018826A1 (en) * 2002-04-08 2006-01-26 Unger Gretchen M Biologic modulations with nanoparticles
US20070098713A1 (en) * 2002-04-08 2007-05-03 Genesegues, Inc. Nanoparticle delivery systems and methods of use thereof
US20060008478A1 (en) * 2002-04-18 2006-01-12 Tadao Ohno Immunoadjuvant
US8623393B2 (en) 2002-04-29 2014-01-07 Gel-Del Technologies, Inc. Biomatrix structural containment and fixation systems and methods of use thereof
US20050163817A1 (en) * 2002-04-29 2005-07-28 Masters David B. Biomatrix structural containment and fixation systems and methods of use thereof
US8771650B2 (en) 2003-05-30 2014-07-08 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Inducible release vehicles
US8771649B2 (en) * 2003-05-30 2014-07-08 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Inducible release vehicles
US20070092480A1 (en) * 2003-05-30 2007-04-26 Thijssen Henricus Matheus W M Inducible release vehicles
US20060167540A1 (en) * 2003-06-17 2006-07-27 Masters David B Encapsulated or coated stent systems
US8465537B2 (en) 2003-06-17 2013-06-18 Gel-Del Technologies, Inc. Encapsulated or coated stent systems
US20110118818A1 (en) * 2003-06-17 2011-05-19 Gel-Del Technologies ,Inc. a corporation Encapsulated or coated stent systems
US8153591B2 (en) * 2003-08-26 2012-04-10 Gel-Del Technologies, Inc. Protein biomaterials and biocoacervates and methods of making and using thereof
US9107937B2 (en) 2003-08-26 2015-08-18 Gel-Del Technologies, Inc. Wound treatments with crosslinked protein amorphous biomaterials
EP1660013A2 (en) * 2003-08-26 2006-05-31 Gel-Del Technologies, Inc. Protein biomaterials and biocoacervates and methods of making and using thereof
US20060073207A1 (en) * 2003-08-26 2006-04-06 Masters David B Protein biomaterials and biocoacervates and methods of making and using thereof
WO2005034852A2 (en) 2003-08-26 2005-04-21 Gel-Del Technologies, Inc. Protein biomaterials and biocoacervates and methods of making and using thereof
EP1660013A4 (en) * 2003-08-26 2011-07-20 Gel Del Technologies Inc Protein biomaterials and biocoacervates and methods of making and using thereof
US20050085922A1 (en) * 2003-10-17 2005-04-21 Shappley Ben R. Shaped filler for implantation into a bone void and methods of manufacture and use thereof
US20080075778A1 (en) * 2004-08-19 2008-03-27 Heller Phillip F Coacervate Microparticles Useful For The Sustained Release Administration Of Therapeutic Agents
WO2006023207A2 (en) * 2004-08-19 2006-03-02 The United States Of America As Represented By The Secretary Of Health And Human Services, Nih Coacervate of anionic and cationic polymer forming microparticles for the sustained release of therapeutic agents
WO2006023207A3 (en) * 2004-08-19 2007-03-08 Us Health Coacervate of anionic and cationic polymer forming microparticles for the sustained release of therapeutic agents
US8728526B2 (en) 2004-08-19 2014-05-20 The United States of America, Represented by Secretary of Department of Health and Human Services, NIH Coacervate microparticles useful for the sustained release administration of therapeutic agents
US7722857B2 (en) 2006-01-06 2010-05-25 Cell-Medicine, Inc. Immunoadjuvant
US20090274763A1 (en) * 2006-01-06 2009-11-05 Cell-Medicine, Inc. Immunoadjuvant
WO2007077629A1 (en) 2006-01-06 2007-07-12 Cell-Medicine, Inc. Immune adjuvant
WO2009028764A1 (en) * 2007-08-24 2009-03-05 Industry-University Cooperation Foundation Hanyang University Thermo-reversible coacervate combination gels for protein delivery
US20100143487A1 (en) * 2007-12-26 2010-06-10 Gel-Del Technologies, Inc. Biocompatible protein-based particles and methods thereof
WO2010065613A2 (en) 2008-12-03 2010-06-10 The Johns Hopkins University Annexina2 as immunological target
EP3115063A2 (en) 2008-12-03 2017-01-11 The John Hopkins University Galectin-3 and annexin-a2 as immunological target

Also Published As

Publication number Publication date Type
WO1995003789A1 (en) 1995-02-09 application

Similar Documents

Publication Publication Date Title
Felt et al. Chitosan: a unique polysaccharide for drug delivery
Jameela et al. Progesterone-loaded chitosan microspheres: a long acting biodegradable controlled delivery system
US4954298A (en) Method for producing microcapsule
Jain The manufacturing techniques of various drug loaded biodegradable poly (lactide-co-glycolide)(PLGA) devices
US4806355A (en) Microencapsulation of living tissue and cells
US5643607A (en) Prolonged release microcapsules
EP0467389B1 (en) Drug delivery system comprising interaction between calcitonin and a hydrophobic biodegradable polymer
Agnihotri et al. Recent advances on chitosan-based micro-and nanoparticles in drug delivery
US5955096A (en) Methods and compositions for enhancing the bioadhesive properties of polymers using organic excipients
US5972389A (en) Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter
Hora et al. Release of human serum albumin from poly (lactide-co-glycolide) microspheres
US4779806A (en) Ultrasonically modulated polymeric devices for delivering compositions
US4756907A (en) Active/passive immunization of the internal female reproductive organs
US6740333B2 (en) Suppository and composition comprising at least one polyethylene glycol
Sinha et al. Chitosan microspheres as a potential carrier for drugs
US6294204B1 (en) Method of producing morphologically uniform microcapsules and microcapsules produced by this method
US6998268B2 (en) Gene preparations
US5656290A (en) Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery
US5891477A (en) Non-steroidal anti-inflammatory agents inhibition of fibrotic response to an implanted device
US5863554A (en) Enhanced uptake drug delivery system
US4732763A (en) Active/passive immunization of the internal female reproductive organs
US6036978A (en) Controlled release polypeptide compositions and methods of treating inflammatory bowel disease
US6413494B1 (en) Composition and pharmaceutical dosage form for colonic drug delivery using polysaccharides
US20030049320A1 (en) Novel in-situ forming controlled release microcarrier delivery system
US5861159A (en) Controlled release of pharmaceutically active substances for immunotherapy

Legal Events

Date Code Title Description
FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
FP Expired due to failure to pay maintenance fee

Effective date: 20100602